Credit: NIH
A newly identified class of compounds recognize a key target in the Ras signaling pathway and could therefore prove useful in treating a range of malignancies, according to research published in Chemistry & Biology.
The lead compound, NSC-658497, targeted the catalytic activation of Ras by an enzyme called SOS1.
NSC-658497 blocked SOS1-mediated molecular signaling in the Ras pathway that causes rapid cell proliferation, tumor development, and cancer.
“While Ras pathway activation is a dominant event happening in many diseases, so far, the immediate signaling module of the Ras pathway has been difficult to target,” said study author Yi Zheng, PhD, of Cincinnati Children’s Hospital in Ohio.
“Most strategies for treatment have been geared toward hitting molecular effectors that are farther downstream. In this study, we have identified synthetic compounds that specifically recognize the catalytic pocket of SOS1 and demonstrated that they are effective inhibitors of Ras signaling in cells. This establishes a novel targeting approach for cancers and Rasopathies that is useful in developing therapeutics.”
Rasopathies include a group of 9 developmental syndromes that are caused by mutations in the Ras pathway (Noonan, LEOPARD, hereditary Gingival fibromatosis type 1, Capillary malformation-AV malformation, Neurofibromatosis type 1, Legius, Costello, Cardio-facio-cutaneous, and autoimmune lymphoproliferative syndromes).
Dysregulation of the Ras pathway (including its SOS1 catalytic activator) is also linked to a number of malignancies, such as breast, pancreatic, and cervical cancers, as well as leukemia.
To find compounds that could target the Ras pathway, Dr Zheng and his colleagues tested 30,000 synthetic molecular compounds in a database maintained by the National Cancer Institute.
The researchers looked for the compounds’ ability to dock with the catalytic site of SOS1, which led them to identify NSC-658497 and derivatives as lead candidates for the development of a prospective drug.
The team then tested NSC-658497 in cell lines of mouse fibroblasts and prostate cancer. These experiments showed the compound successfully blocked SOS1-to-Ras signaling and the proliferation of cancer cells.
Dr Zheng said one of the researchers’ next steps is to transform NSC-658497 into a drug that can be administered to a living organism so the team can begin testing the inhibitor in mouse models of different Rasopathies and cancers.
One of the targeted approaches the researchers plan to explore is whether NSC-658497 might be most promising in individuals who have a subset of disease in which SOS1 is significantly overexpressed or mutated.
